Glaucoma is a family of diseases characterized by degenerative optic neuropathy usually related to elevation of lOP and retinal ganglion cells loss. Despite recent advances in identifying genes related to glaucoma our understanding of the pathophysiology of the disease is still limited. The long-term objective of this project is to determine the molecular mechanisms leading to the development of retinal pathology in glaucoma. To achieve this goal, differential gene expression in whole retina of mice (both glaucomatous and non-glaucomatous) of various ages (from 3 to 18 months of age) will be determined using microarray gene analysis. In addition, differential gene expression among areas of the retina with various degrees of RGC loss in aged glaucomatous animals (15 to 18 months of age) will be determined using the same methodology. Retinal gene expression will also be correlated to the lOP exposure history in glaucomatous animals. All microarray analysis results will be confirmed at the RNA as well as the protein level. Through preliminary experiments, a number of genes whose expression changes with the progression of glaucomatous retinal pathology have already been identified. This project will also investigate whether changes in expression of two of these genes, ceruloplasmin (cp) and complement component 1q (C1q), have a beneficial/protective or detrimental/destructive role in glaucoma. This will be achieved by generating congenic animals in the DBA/2 glaucomatous background that carry knockout mutations in these two genes. The up-regulation in the level of expression of the cp and C1q proteins will also be confirmed in archival tissue material from experimental primate glaucoma and patients with glaucoma by immunohistochemistry. Completion of this project will increase our understanding of the molecular pathways within the retina involved in the pathogenesis of glaucoma and might allow the identification of novel targets for development of new therapeutic approaches.